Radiopaque, non-biodegradable, water-insoluble iodinated benzyl ethers of poly(vinyl alcohol), preparation method thereof, injectable embolizing compositions containing thereof and use thereof

ABSTRACT

The invention concerns a radiopaque, non-biodegradable, water-insoluble iodinated benzyl ether of poly(vinyl alcohol) consisting of a PVA having covalently grafted thereon iodinated benzyl groups comprising 1-4 iodine atoms per benzyl group, a process for preparing the same comprising reacting a 0-100% hydrolyzed PVA with a iodinated benzyl derivative comprising 1-4 iodine atoms per benzyl group in a polar aprotic solvent in the presence of a base in anhydrous conditions. Said iodo-benzylether-PVA is particularly useful as embolic agent in an injectable embolizing composition. The invention also concerns an injectable embolizing composition comprising said iodo-benzylether-PVA and capable of forming a cohesive mass upon contact with a body fluid by precipitation of the iodo-benzylether-PVA. Said injectable embolizing composition is particularly useful for forming in-situ a cohesive mass in a blood vessel or into a tumor. The invention further concerns a coating composition containing said iodo-benzylether-PVA and capable of forming a radiopaque coating on a medical device. The invention further concerns particles formed of said iodo-benzylether-PVA.

RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §371 ofInternational Application No. PCT/EP2011/053536, having an InternationalFiling Date of Mar. 9, 2011, which claims priority to EP Application No.10156039.9, filed Mar. 10, 2010, the contents of all of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to radiopaque, non-biodegradable,water-insoluble iodinated polymers, and more particularly to radiopaque,non-biodegradable, water-insoluble, iodinated benzyl ethers ofpoly(vinyl alcohol), to their use as embolizing agents, to a process forproducing thereof, to injectable embolizing compositions containingthereof and the uses thereof, to coating compositions containing thereofand to micro- and nanoparticles made thereof.

BACKGROUND OF THE INVENTION

The embolization of a blood vessel is important inpreventing/controlling bleeding (e.g., organ bleeding, gastrointestinalbleeding, vascular bleeding, bleeding associated with an aneurysm) or toablate diseased tissue (e.g., tumors, etc.) by cutting off its bloodsupply.

Endovascular embolization of blood vessels is known to be conducted asalternative to surgical interventions for a variety of purposesincluding the endovascular treatment of tumors, the treatment of lesionssuch as aneurysms, arteriovenous malformations, arteriovenous fistula,uncontrolled bleeding and the like.

Endovascular embolization of blood vessels is accomplished via cathetertechniques which permit the selective placement of the catheter at thevascular site to be embolized.

Recent techniques proposed to embolize blood vessels by using injectableembolizing compositions including polymeric materials as embolizingagents.

The use of embolizing compositions in the treatment of aneurysms orarteriovenous malformations (AVMs) is advantageous since the polymericmaterials fill the inside of the aneurysms or AVM and solidify in theshape of the aneurysm or AVM, therefore the aneurysm or AVM will becompletely excluded from the blood circulation.

It is also known that injectable embolizing compositions containingpolymeric materials as embolizing agents may be used for treating tumorsby direct puncture.

In such a case, the embolizing composition is directly injected into thetumoral tissue or the vascular bed surrounding the tumor via a needletechnology.

Known polymeric materials employed in embolizing compositions includefor example those wherein a preformed polymer in situ precipitates froma carrier solution at the vascular site or into the tumor.

In embolizing compositions, the preformed polymer must be selected to becapable of rapid precipitation to form a well defined cohesive solid orsemi-solid mass, space-filling material upon contact with blood or anyother body aqueous environment in a tissue.

Additionally, these compositions should be sterile, stable,biocompatible, and further highly radiopaque to allow for an efficientimaging using current radiology techniques.

This last property is necessary in order to visualize the embolizingcomposition during injection, deposition into the vascular site, andclinical follow-up.

A number of documents disclose liquid formulations intended for theembolization of blood vessels and containing a water-insoluble,organo-soluble biocompatible preformed polymer dissolved in abiocompatible water-miscible organic solvent, and a solidwater-insoluble biocompatible radiopaque contrast agent such astantalum, tantalum oxide, tungsten, bismuth trioxide and barium sulfate.

These known radiopaque embolizing compositions, precipitating uponcontact with blood, are simple physical mixtures of a preformed polymerdissolved in a water-miscible organic solvent and a conventionalradiopaque contrast agent.

U.S. Pat. No. 5,580,568 discloses compositions suitable for use inembolizing blood vessels which comprise a cellulose diacetate polymer, abiocompatible solvent such as DMSO and a water insoluble contrast agentsuch as tantalum, tantalum oxide and barium sulfate.

U.S. Pat. No. 5,851,508 discloses compositions suitable for use inembolizing blood vessels which comprises an ethylene vinyl alcoholcopolymer, a biocompatible solvent such as DMSO and a water insolublecontrast agent such as tantalum, tantalum oxide and barium sulfate.

U.S. Pat. No. 5,695,480 discloses compositions for use in embolizingblood vessels which comprise a biocompatible polymer selected fromcellulose acetates, cellulose acetate propionates, cellulose acetatebutyrates, ethylene vinyl alcohol copolymers, hydrogels,polyacrylonitrile, polyvinylacetate, nitrocellulose, copolymers ofurethane/carbonate, copolymers of styrene/maleic acid and mixturesthereof, a biocompatible solvent such as DMSO, ethanol and acetone, anda contrast agent such as tantalum, tantalum oxide, tungsten and bariumsulfate.

However, in these formulations, the radiopaque contrast agent issuspended in the polymer solution, so that these embolizing compositionsare heterogeneous dispersions.

Thus, permanent radiopacity may not be ensured with these compositionsbecause chemical incorporation of the contrast agent into the polymerstructure is not achieved and sedimentation of the contrast agent duringcatheterization or slow release with time in the surrounding areas couldoccur, which would be a major drawback for clinical follow-up and couldlead to serious toxic-effects.

A well-known commercially available formulation of this type is ONYX™, amixture of ethylene-vinyl alcohol copolymer (EVOH) dissolved in DMSO,with micronized tantalum powder in the liquid polymer/DMSO mixture toprovide fluoroscopic visualization.

ONYX™ is delivered through a microcatheter to the target lesion underfluoroscopic control.

Upon contact with body fluid (i.e. blood), the solvent (DMSO) rapidlydiffuses away causing in-situ precipitation of the polymer in thepresence of the radiopaque contrast agent, thus forming a radiopaquepolymeric implant.

ONYX™ is available in a range of liquid viscosities intended to havedelivery and precipitation characteristics optimized for the type oflesion being treated.

However, these formulations have the following drawbacks.

These formulations need careful preparation before use, which is timeconsuming and may lead to application errors.

Further, since the radiopaque contrast agent is suspended in the polymersolution, homogeneous radiopacity may not be ensured with respect topossible sedimentation during embolization. The radiopaque contrastagent also limits non-invasive follow-up imaging by CT scanning becauseof beam-hardening artifacts. Furthermore, the entrapment of the metallicradiopaque contrast agent is not ensured so that phase separation mayoccur.

As a consequence, the radiopaque contrast agent does not reflect theposition of the polymer and implant visibility may change duringradiological imaging follow-up studies. Released metallic radiopaquecontrast agents are potentially toxic.

To overcome the drawbacks of formulations containing a radiopaque agentin suspension in the polymer solution, some of the present inventorshave focused on the need to provide an intrinsically radiopaque polymerfor use as embolizing agent in liquid embolizing compositions.

For this purpose, they have synthesized a iodinated poly(vinyl alcohol)(I-PVA) by grafting iodobenzoyl chloride to poly(vinyl alcohol) viaester linkages and tested such an I-PVA polymer.

The results obtained when such an I-PVA is used in liquid embolizingcompositions were reported in a number of publications (see O. Jordan etal., 19th European Conference on Biomaterials, 2005, Sorrento, Italia,“Novel organic vehicles for the embolization of vascular malformationsand intracranial aneurysms”; O. Jordan et al., Transactions of the 7thWorld Biomaterials Congress, Sydney, Australia, 706, 2004, “NovelRadiopaque Polymer for Interventional Radiology”; O. Jordan et al.,American Society of Neuroradiology 42nd annual meeting, Seattle, Jun.5-11, 2004, “Liquid Embolization of Experimental Wide-Necked Aneurysmswith Polyvinyl Alcohol Polymer: A New, Nonadhesive, Iodine-ContainingLiquid Embolic Agent”; O. Dudeck, O. Jordan et al., Am. J. Neuroradiol.,27:1900-1906, 2006, “Organic solvents as vehicles for precipitatingliquid embolics”; O. Dudeck, O. Jordan et al.; Am. J. Neuroradiol., 27:1849-55, October 2006, “Embolization of Experimental Wide-NeckedAneurysm with Iodine-Containing Polyvinyl Alcohol Solubilized in aLow-Angiotoxicity Solvent”; O. Dudeck, O. Jordan et al., J. Neurosurg.104: 290-297, February 2006, “Intrinsically radiopaque iodine-containingpolyvinyl alcohol as a liquid embolic agent: evaluation in experimentalwide-necked aneurysms”) without identifying the I-PVA used.

However, this I-PVA lacks stability with respect to hydrolysis, and whenused as embolizing agent, undergoes partial degradation leading topotentially toxic degradation products in the body over time.

Moreover, since the embolic mass is expected to stand for a longduration, sustainable attachment of the iodinated markers is required.

Therefore, the present inventors have focused their research on the needto provide a new iodinated poly(vinyl alcohol) which has an improvedstability, and have surprisingly found a new iodinated poly(vinylalcohol) which has not only an improved stability with respect tohydrolysis, but which is also expected to provide liquid embolizingcompositions having higher concentration of embolizing agent, andtherefore lower volume of organic solvent due to its unexpected lowviscosity in solution, and have thus achieved the present invention.

SUMMARY OF THE INVENTION

According to a first aspect, the present invention provides aradiopaque, non-biodegradable, water-insoluble iodinated benzyl ether ofpoly(vinyl alcohol) (iodo-benzylether-PVA) consisting of a poly(vinylalcohol) having covalently grafted thereon iodinated benzyl groupscomprising 1-4 iodine atoms per benzyl group.

According to a second aspect, the present invention provides a processfor preparing the iodo-benzylether-PVA of the present invention, saidprocess comprising reacting a 0-100% hydrolyzed poly(vinyl alcohol) as astarting PVA with a iodinated benzyl derivative comprising 1-4 iodineatoms per benzyl group in a polar aprotic solvent in the presence of abase in anhydrous conditions.

According to a third aspect, the present invention provides a use of theiodo-benzylether-PVA of the present invention as an embolic agent in aninjectable embolizing composition.

According to a fourth aspect, the present invention provides aninjectable embolizing composition comprising the iodo-benzylether-PVA ofthe present invention and a water-miscible, biocompatible solventsolubilizing the iodo-benzylether-PVA, wherein the concentration of theiodo-benzylether-PVA in the composition is selected in the range of 5-65w/w % so that the composition is capable of forming a cohesive mass uponcontact with a body fluid by precipitation of the iodo-benzylether-PVA.

According to a fifth aspect, the present invention provides a use of theinjectable embolizing composition of the present invention for formingin-situ a cohesive mass in a blood vessel such as arteriovenousmalformation (AVMs) or vascular aneurysms.

According to a sixth aspect, the present invention provides a use of theinjectable embolizing composition of the present invention for formingin-situ a cohesive mass into a tumor.

According to a seventh aspect, the present invention provides a use ofthe injectable embolizing composition of the present invention forforming in-situ a semi-solid implant into a tumor for treating the tumorby hyperthermia.

According to a eighth aspect, the present invention provides a use ofthe injectable embolizing composition of the present invention forforming in-situ a semi-solid implant for treating urinary incontinence.

According to a ninth aspect, the present invention provides a coatingcomposition for forming a coating on a medical device comprising theiodo-benzylether-PVA of the present invention and a solvent solubilizingthe iodo-benzylether-PVA, wherein the concentration of theiodo-benzylether-PVA in the composition is selected in the range of 5-65w/w % so that the composition is capable of forming a radiopaque coatingafter application on a medical device and solvent evaporation.

According to a tenth aspect, the present invention provides particles,selected from microparticles and nanoparticles, formed of theiodo-benzylether-PVA of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the ¹H-NMR spectrum of 2,3,5-triiodobenzylether ofpoly(vinyl alcohol) of the present invention prepared according toExample 1.

FIG. 2 shows the ¹H-NMR spectrum of 4-iodobenzylether of poly(vinylalcohol) of the present invention prepared according to Example 2.

FIG. 3 a is a photograph showing precipitation in water of2,3,5-triiodobenzylether of poly(vinyl alcohol) prepared according toExample 1 dissolved at a concentration of 10% w/w in N-methylpyrrolidone(NMP).

FIG. 3 b is a photograph showing precipitation in water of2,3,5-triiodobenzylether of poly(vinyl alcohol) prepared from PVA 13 kDaaccording to Example 1, dissolved at a concentration of 33% w/w in NMP.

FIG. 4 is a photograph showing precipitation in water of4-iodobenzylether of poly(vinyl alcohol) prepared from PVA 13 kDaaccording to Example 2, dissolved at a concentration of 33% w/w in DMSO.

FIG. 5 represents a graph showing the change of viscosity [mPa·s] of twosolutions containing a iodo-benzylether-PVA of the present inventionprepared from PVA 13 kDa in relation to a change of the concentration (%w/w) of the iodo-benzylether-PVA in solution.

FIG. 6 represents a graph illustrating the radiopacity of two injectableembolizing compositions of the present invention, as compared with theradiopacity of Onyx™ 18 and Onyx™ 34.

FIG. 7 a is a photograph showing embolization of an aneurysm model withan injectable embolizing composition of the present invention containing33% w/w of 2,3,5-triiodobenzylether of poly(vinyl alcohol) dissolved inNMP.

FIG. 7 b is a photograph showing embolization of an aneurysm model withan injectable embolizing composition of the present invention containing33% w/w of 4-iodobenzylether of poly(vinyl alcohol) dissolved in NMP.

FIG. 7 c is a photograph showing embolization of an aneurysm model withOnyx™ 34 commercial embolizing composition.

FIG. 8 shows the ¹H-NMR spectrum of MTIB-PVA 47 kDa of the presentinvention prepared according to Example 13.

FIGS. 9 a et 9 b are photographic (FIG. 9 a) and fluoroscopic x-ray(FIG. 9 b) images of plugs obstructing hydrogel model obtained from aninjectable embolizing formulation of the present invention at twoconcentrations of 30% and 35% w/w in NMP of2,3,5-tri-iodobenzylether-PVA 47 kDa (DS=58%) as reported in Example 14,wherein saline flows from the right to the left.

FIG. 10 is a photograph showing a plug obtained following injection intohydrogel model of a mixture of 4-mono-iodobenzylether-PVA 61 kDa(DS=67%) and 2,3,5-tri-iodobenzylether-PVA 61 kDa (DS=58%) in 50:50 wt %at a total concentration of 33 wt % in NMP as reported in Example 14,wherein saline flows from the right to the left.

FIG. 11 a is a photograph showing a viscous injectable embolizingformulation of the present invention containing4-mono-iodobenzylether-PVA 47 kDa (DS=56%) at a concentration of 33 wt %in NMP loaded with superparamagnetic iron nanoparticles at aconcentration of 20% w/V, as reported in Example 16.

FIG. 11 b is a photograph showing a hyperthermic semi-solid smoothimplant formed after injection of the viscous injectable embolizingformulation of the present invention shown in FIG. 11 a into hydrogelmodel, as reported in Example 16.

FIG. 12 represents a graph illustrating the temperature increaseobtained with the hyperthermic implant shown in FIG. 11 b under exposureto an alternating magnetic field.

FIG. 13 represents a graph illustrating doxorubicine released from aradiopaque plug (n=3, error bars indicate standard error of the mean(sem)) in saline medium, formed from an injectable embolizingformulation of the present invention as reported in Example 17.

FIG. 14 represents a catheter coated with a coating composition of thepresent invention as reported in Example 18.

FIG. 15 represents a graph illustrating the evolution of the absorbanceof nanoparticle degradation products for the 4-mono-iodobenzylether-PVA47 kDa and 4-mono-iodobenzoate-PVA 47 kDa as reported in Example 20.1.

FIG. 16 represents a graph illustrating the evolution of the absorbanceof nanoparticle degradation products for the2,3,5-tri-iodobenzylether-PVA 13 kDa and 2,3,5-tri-iodobenzoate-PVA 13kDa as reported in Example 20.2.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

It is to be noted that in the present description and claims, theiodinated benzyl ether of poly(vinyl alcohol) of the present inventionwill be designed as “iodo-benzylether-PVA of the present invention”.

The iodo-benzylether-PVA of the present invention is a radiopaque,non-biodegradable, water-insoluble iodinated benzyl ether of poly(vinylalcohol) consisting of a poly(vinyl alcohol) having covalently graftedthereon iodinated benzyl groups comprising 1-4 iodine atoms per benzylgroup via ether linkages.

The degree of substitution (DS) of the iodo-benzylether-PVA of thepresent invention is not particularly limited.

However, in order to provide an appropriate radiopacity to theiodo-benzylether-PVA of the present invention, the degree ofsubstitution (DS) is preferably of at least 0.2.

In a preferred embodiment, the degree of substitution is of at least0.4, and more preferably of at least 0.5.

The degree of substitution (DS) is defined asDS=x/(x+y)wherein

-   -   x represents the number of grafted repeating units, and    -   x+y represents the total number of repeating units (grafted        repeating units and non-grafted repeating units),        as calculated from the integration of the NMR lines of the        iodo-benzylether-PVA of the present invention.

For clarifying what is meant by grafted and non-grafted repeating unitsin the iodo-benzylether-PVA of the present invention, a graftedrepeating unit may be represented by

wherein n represents the number of iodine atoms on benzyl group, and anon-grafted repeating unit may be represented by

The iodine content (% I) of the iodo-benzylether-PVA of the presentinvention is not particularly limited, but should preferably be of atleast 20% (w/w) for making it sufficiently radiopaque.

In a preferred embodiment of the present invention, theiodo-benzylether-PVA has a iodine content of at least 40% (w/w).

The iodo-benzylether-PVA of the present invention may be either aiodo-benzylether-PVA wherein all the grafted iodinated benzyl groups areidentical, or may be a iodo-benzylether-PVA, wherein the graftediodinated benzyl groups are two or more different iodinated benzylgroups having different number of iodine atoms.

When the iodo-benzylether-PVA is grafted with identical iodinated benzylgroups, the iodine content (% I) of the iodo-benzylether-PVA of thepresent invention may be calculated from the degree of substitution (DS)as follows:

${\%\mspace{14mu} I} = {\frac{{DS} \times M_{({Iodine})} \times n}{\lbrack {M_{({{non}\text{-}{grafted}})} \times ( {1 - {DS}} )} \rbrack + \lbrack {M_{({grafted})} \times {DS}} \rbrack} \times 100}$whereinM_((iodine)) represents the atomic mass of iodine atom (i.e. ˜127)n represents the number of iodine atoms per benzyl group (i.e. from 1 to4)M_((non-grafted)) represents the molar mass of a non-grafted repeatingunit

-   -   to (i.e. ˜44)        M_((grafted)) represents the molar mass of a grafted repeating        unit (for example    -   ˜260 when the benzyl group has only one iodine as substituent,    -   ˜386 when the benzyl group has only two iodine atoms as        substituents,    -   ˜512 when the benzyl group has only three iodine atoms as        substituents,    -   and ˜638 when the benzyl group has only four iodine atoms as        substituents).

When the iodo-benzylether-PVA of the present invention is grafted withtwo or more different iodinated benzyl groups having different number ofiodine atoms, the iodine content (% I) of the iodo-benzylether-PVA ofthe present invention is the sum of the contributions of each type ofgrafted iodinated benzyl groups.

Therefore, the iodine content (% I) of a iodo-benzylether-PVA graftedwith two or more different iodinated benzyl groups having differentnumber of iodine atoms may be calculated by determining the degree ofsubstitution (DS) for each type of iodinated benzyl groups, then bycalculating the iodine content (% I) based on said DS using the aboveformula for each type of iodinated benzyl groups, and finally by addingthe iodine contents (% I) calculated for each type of iodinated benzylgroups.

For instance, for a iodo-benzylether-PVA of the present invention havingboth mono-iodobenzyl groups and tri-iodobenzyl groups, the iodinecontent (% I) is the sum of the % I for the mono-iodobenzyl groups (n=1)plus the % I for the tri-iodobenzyl groups.

The iodine content may also be determined or confirmed by elementalanalysis.

According to the present invention, the iodinated benzyl groups graftedon the poly(vinyl alcohol) must comprise 1-4 iodine atoms per benzylgroup.

It is to be noted that in the present invention, the benzyl group mayfurther comprise other substituents such as amino, amide, ester and/orcarbamoyl groups in addition to iodine atom(s), but in a particularlypreferred embodiment of the present invention, the benzyl groupcomprises only iodine atom(s) as substituent(s).

In one preferred embodiment of the present invention wherein all thegrafted iodinated benzyl groups are identical, each benzyl groupcomprises only one iodine atom as substituent, and more preferably oneiodine atom on the C4-position of the benzyl group.

In another preferred embodiment of the present invention wherein all thegrafted iodinated benzyl groups are identical, each benzyl groupcomprises only three iodine atoms as substituents, and more preferablythree iodine atoms on the C-2, C-3 and C-5 positions of the benzylgroup.

However, each benzyl group may comprise from 1 to 4 iodine atoms, in anypositions on the benzyl group.

In a preferred embodiment wherein the grafted iodinated benzyl groupsare different iodinated benzyl groups having a different number ofiodine atoms, the iodo-benzylether-PVA of the present invention havegrafted thereon both iodinated benzyl groups comprising one iodine atomon the C4-position and iodinated benzyl groups comprising three iodineatoms on the C-2, C-3 and C-5 positions.

However, the iodo-benzylether-PVA of the present invention may havegrafted thereon other types and combinations of iodinated benzyl groups,provided that said iodinated benzyl groups comprises 1-4 iodine atomsper benzyl group.

The average molar mass (M) of iodo-benzylether-PVA of the presentinvention is not particularly limited, and has to be determineddepending on the chosen application.

Molar mass of the iodo-benzylether-PVA of the present invention may beeasily controlled by appropriately selecting the molar mass (M) of thestarting PVA polymer to be grafted in the process for preparing theiodo-benzylether-PVA of the present invention.

It is to be noted that a iodo-benzylether-PVA having a too high molarmass would not be appropriate for use as embolizing agent in anembolization composition because it would lead to an embolizationcomposition too viscous for being injected via a catheter, and aiodo-benzylether-PVA having a too low molar mass would be notappropriate for use as embolizing agent in a liquid embolizingcomposition because the iodo-benzylether-PVA would not precipitate as acohesive mass forming a solid or semi-solid embolic implant.

Further, it is to be noted that a iodo-benzylether-PVA having a highmolar mass and therefore providing a high viscosity in solution is notpreferable when used as embolizing agent in an embolizing compositionbecause the embolizing composition should have a low concentration ofembolizing agents in a high volume of solvent, which is notadvantageous.

The average molar mass (M) of the iodo-benzylether-PVA of the presentinvention depends on the molar mass of the starting PVA polymer used toprepare the iodo-benzylether-PVA of the present invention and on thedegree of substitution of the iodo-benzylether-PVA of the presentinvention.

The iodo-benzylether-PVA of the present invention may be prepared by anetherification reaction of PVA with a iodinated benzyl derivative.

More particularly, the iodo-benzylether-PVA of the present invention maybe prepared by a process comprising reacting a 0-100% hydrolyzedpoly(vinyl alcohol) (starting PVA) with a iodinated benzyl derivativecomprising 1-4 iodine atoms per benzyl group in a polar aprotic solventin the presence of a base in anhydrous conditions.

Poly(vinyl alcohol) (PVA) is a polymeric chain made of carbon atoms withpendant hydroxyl groups, which may also contain some pendant acetylgroups.

In the process of the present invention, a 0% hydrolyzed poly(vinylalcohol) means a PVA containing 0% of pendant hydroxyl groups and 100%of pendant acetyl groups on the polymeric chain.

In the process of the present invention, a 100% hydrolyzed poly(vinylalcohol) means a PVA containing only pendant hydroxyl groups.

It is to be noted that during the grafting reaction, pendant acetylgroups which may be present in the starting PVA are eliminated so thatthe iodo-benzylether-PVA of the present invention contains only pendanthydroxyl groups and pendant grafted iodinated benzyl ether groups.

In a particularly preferred embodiment of the present invention, theprocess for preparing the iodo-benzylether-PVA of the present inventioncomprises reacting a 75-100% hydrolyzed poly(vinyl alcohol) as thestarting PVA with the iodinated benzyl derivative.

The average molar mass (M) of the starting PVA used in the process ofthe present invention is not particularly limited, and has to bedetermined depending on the average molar mass (M) expected for thefinal iodo-benzylether-PVA, depending on the chosen application.

However, performing the process of the present invention with a PVAhaving a too high molar mass or a too low molar mass would not lead to aiodo-benzylether-PVA appropriate for use as embolizing agent in a liquidembolizing composition.

Therefore, the average molar mass (M) of the starting PVA for preparinga iodo-benzylether-PVA for use as embolizing agent in a liquidembolizing composition is preferably not smaller than 5,000 Daltons andnot greater than 200,000 Daltons, more preferably in the range from10,000 to 130,000 Daltons, and still more preferably in the range from10,000 to 50,000 Daltons.

For example, commercial PVA which may be used as starting PVA in theprocess of the present invention may be a PVA of pharmaceutical gradeobtained from Sigma-Aldrich® Co. having a weight-average molar mass (Mw)of 13,000-23,000 Daltons and a degree of hydrolysis of 87-89%.

However, any commercial PVA having any degree of hydrolysis may be usedfor preparing the iodo-benzylether-PVA of the present inventionaccording to the process of the present invention.

In the process of the present invention, the iodinated benzyl derivativeis selected as a reagent to be grafted depending on theiodo-benzylether-PVA to be obtained, and may be for example a iodinatedbenzyl chloride, a iodinated benzyl bromide or a iodinated benzylmesylate.

In a preferred embodiment, a iodo-benzylether-PVA comprising one iodineatom on the C4-position of all the benzyl groups may prepared by usingcommercial 4-iodobenzyl bromide (for example obtained fromSigma-Aldrich® Co.) as iodinated benzyl derivative.

In another preferred embodiment, a iodo-benzylether-PVA comprising threeiodine atoms on the C-2, C-3 and C-5 positions on all the benzyl groupsmay be prepared by using 2,3,5-triiodobenzyl bromide as iodinated benzylderivative.

2,3,5-Triiodobenzyl derivatives may be easily prepared as reported inthe experimental part in Preparation Examples 1-4.

In another embodiment of the present invention, a iodo-benzylether PVAcomprising both benzyl groups including one iodine atom on theC4-position and benzyl groups including three iodine atoms on the C-2,C-3 and C-5 positions may be prepared by using a mixture of 4-iodobenzylbromide and 2,3,5-triiodobenzyl bromide as iodinated benzyl derivative.

However, a iodo-benzylether-PVA of the present invention having graftedthereon different benzyl groups may be prepared by using any mixture oftwo or more different iodinated benzyl derivatives comprising 1-4 iodineatoms per benzyl group.

The iodinated benzyl derivatives which may be used in the process of thepresent invention are either commercially available or may be easilyprepared by the skilled person, for example from the correspondingiodinated benzoic acid or the corresponding iodinated benzyl alcoholaccording to conventional methods or according to methods based on thosereported in the experimental part in Preparation Examples 1-4.

Examples of the polar aprotic solvent for use in the synthesis processof the present invention may include DMSO (dimethylsulfoxide), NMP(N-methyl-pyrrolidone) and THF (tetrahydrofuran).

Examples of the base for use in the process of the present invention mayinclude NaOH, KOH and NaH,

In a preferred embodiment of the process of the present invention, thepolar aprotic solvent is NMP and the base is NaOH.

Kinetics studies have shown that the degree of substitution (DS) isdependent on the time of the grafting reaction and usually reaches amaximum value after approximately ½-15 hours so that the degree ofsubstitution (DS) may be easily fixed by controlling the time of thegrafting reaction.

If required, the iodo-benzylether-PVA of the present invention obtainedby this process may be further purified by conventional techniquesincluding, but not limited to,precipitation/solubilization/precipitation cycles to reach the degree ofpurity required.

The iodo-benzylether-PVA of the present invention is useful asembolizing agent in an injectable embolizing composition.

The injectable embolizing composition of the present invention comprisesthe iodo-benzylether-PVA of the present invention and a water-miscible,biocompatible solvent solubilizing the iodo-benzylether-PVA of thepresent invention.

Because the viscosity of a polymer solution is known to be verysensitive to polymer molar mass, particularly at high concentration, itis important to appropriately select the molar mass of theiodo-benzylether-PVA contained in the embolizing composition in orderthat it is not too high and not too low for this application.

For example, with respect to its molar mass, a preferableiodo-benzylether-PVA for use as embolic agent in an embolizingcomposition may be obtained by using, as starting PVA, a PVA having amolar mass not smaller than 5,000 Daltons and not greater than 200,000Daltons, preferably in the range from 10,000 to 130,000 Daltons, andmore preferably in the range from 10,000 to 50,000 Daltons.

The concentration of a polymer in solution also affects not only theviscosity of the polymer solution but also the precipitation behaviourof the polymer.

The concentration of the iodo-benzylether-PVA of the present inventionin the embolizing composition is selected in the range of 5-65 w/w %,said selection being dependent on the targeted viscosity of theembolizing composition, which itself depends on the average molar massof the iodo-benzylether-PVA of the present invention used in theembolizing composition.

According to the present invention, said selection of the concentrationof the iodo-benzylether-PVA of the present invention must lead to anembolizing composition which is injectable, i.e. which is not tooviscous for being injected, and further which is capable of forming acohesive solid or semi-solid mass upon contact with an aqueous mediasuch as a body fluid by precipitation of the iodo-benzylether-PVA.

Preferably, the concentration of the iodo-benzylether-PVA of the presentinvention is selected to be as high as possible in order to provide anembolizing composition having a reduced quantity of solvent.

In a particularly preferred embodiment of the present invention, theconcentration of the iodo-benzylether-PVA of the present invention inthe embolizing composition is selected in the range of 20-50 w/w %.

Further, it is preferable that the iodo-benzylether-PVA of the presentinvention used in the injectable embolizing composition of the presentinvention has a iodine content (% I) of at least 20% (w/w), and morepreferably of at least 40% (w/w) in order to provide an improvedradiopacity to the embolizing composition and also to the embolic massformed by precipitation of the iodinated-benzylether-PVA upon contact ofthe embolizing composition with a body fluid.

The water-miscible, biocompatible solvent used in the injectableembolizing composition of the present invention is not particularlylimited, provided that it solubilizes the iodo-benzylether-PVA to form ahomogeneous solution.

In a preferred embodiment, the water-miscible, biocompatible solvent isselected from dimethylsulfoxide, N-methylpyrrolidone, glycofurol,pyrrolidone, ethanol, propylene glycol, polyethylene glycol, Solketal™,glycerol formal, tetrahydrofurfuryl alcohol, dimethyl isosorbide, ethyllactate, hydroxyethyllactamide and N,N-dimethylacetamide, and morepreferably from dimethylsufoxide (DMSO), N-methylpyrrolidone (NMP) andglycofurol.

According to an embodiment of the present invention, the injectableembolizing composition of the present invention comprises oneiodo-benzylether-PVA of the present invention.

In a preferred embodiment, the iodo-benzylether-PVA of the presentinvention contained in the injectable embolizing composition of thepresent invention is a iodo-benzylether-PVA, wherein each benzyl groupcomprises one iodine atom on C-4 position (called“4-mono-iodobenzylether-PVA” or “MIB-PVA” below).

In another preferred embodiment, the iodo-benzylether-PVA of the presentinvention contained in the injectable embolizing composition of thepresent invention is a iodo-benzylether-PVA wherein each benzyl groupcomprises 3 iodine atoms on C-2, C-3 and C-5 positions (called“2,3,5-tri-iodo-benzyelther-PVA” or “TIB-PVA” below).

According to another embodiment of the present invention, the injectablecomposition of the present invention may comprise two or more differentiodo-benzylether-PVAs of the present invention having different numberor different position of iodine atoms, provided that the totalconcentration of the iodo-benzylether-PVAs of the present inventioncontained in the injectable embolizing composition is selected in therange of 5-65 w/w %.

In a preferred embodiment, the injectable embolizing composition of thepresent invention contains 4-mono-iodobenzylether PVA (MIB-PVA) and2,3,5-tri-iodobenzylther-PVA (TIB-PVA) in variable proportions.

The viscosity and mechanical properties of iodo-benzylether-PVA, basedon, for instance, 4-monoiodo-benzylether-PVA (MIB-PVA) or2,3,5-triiodo-benzylether-PVA (TIB-PVA) are quite different.

4-Monoiodo-benzylether-PVA (MIB-PVA) is a softer material than2,3,5-triiodo-benzylether-PVA (TIB-PVA), it is less fragile and brittledue to its lower glass transition temperature (Tg of MIB-PVA: 55° C.,TIB-PVA: 111° C.).

In addition, solutions of 2,3,5-triiodo-benzylether-PVA (TIB-PVA) in NMPtend to precipitate faster in aqueous environment than4-monoiodo-benzylether PVA (MIB-PVA).

Therefore, mixtures of MIB-PVA and TIB-PVA in variable proportions canbe used to adjust the mechanical properties of the final precipitatedimplant.

For instance, equal proportions of MIB-PVA and TIB-PVA dissolved in NMPshow formulation viscosity, precipitation time and mechanical propertiesintermediate between that of MIB-PVA and TIB-PVA.

Blend of MIB-PVA:TIB-PVA can therefore generate a family of liquidembolizing compositions, as illustrated in the Example 14.

Tailoring implant properties can also be obtained using PVA polymersbased on two or more kind of iodinated repeating units.

For instance, as illustrated in Example 13, PVA polymer grafted with MIBand TIB can be obtained by mixing in the reaction vial equal molarquantities of mono-iodobenzyl derivative and tri-iodobenzyl derivative.The resulting copolymer MTIB-PVA shows a close to 50:50 molar ratio of4-mono-iodobenzylether and 2,3,5-tri-iodobenzylether grafted groups,corresponding to a 38:62 MIB:TIB mass ratio.

Such a copolymer MTIB-PVA has a glass transition temperature (Tg=68° C.)intermediate between that of MIB-PVA and TIB-PVA, and Example 15 showsthat precipitation also results in intermediate properties between thatof MIB-PVA and TIB-PVA.

Likewise, based on copolymers, a whole family of formulations can beobtained, tailoring liquid embolic properties by adapting copolymermolar mass, concentration and MIB/TIB ratio.

A man skilled in the art will be capable to determine easily if thecomposition containing the selected concentration of theiodo-benzylether-PVA of the present invention and the selectedwater-miscible, biocompatible solvent is appropriate for use as anembolizing composition by carrying out a precipitation test of thecomposition in water.

The injectable embolizing composition of the present invention isparticularly useful when used for forming in-situ a cohesive solid orsemi-solid mass in a blood vessel or into a tumor for treating human orother mammalian subjects.

When the embolizing composition of the present invention is used forembolizing blood vessels, in particular for treating lesions such asaneurysms, arteriovenous malformations, arteriovenous fistula, andtumors, it is introduced into the blood vessel via a catheter deliverymeans under fluoroscopy so that after precipitation of theiodo-benzylether-PVA, the blood vessel is embolized by the embolic massformed by the precipitated iodo-benzylether-PVA.

When the embolizing composition of the present invention is used in thetreatment of tumors by direct puncture, it is directly injected into thetumoral tissue via a needle technology so that after precipitation ofthe iodo-benzylether-PVA, tumor is filled with the embolic mass formedby the precipitated iodo-benzylether-PVA.

The particular amount of the embolizing composition employed is dictatedby the total volume of the vasculature or tissue to be embolized, theconcentration of the iodo-benzylether-PVA, the rate of precipitation ofthe iodo-benzylether-PVA, etc.; the determination of such factors lieswell within the competence of a person skilled in the art.

In an embodiment of the present invention, the injectable embolizingcomposition of the present invention comprises drugs orbiopharmaceuticals.

The injectable embolizing composition including drugs orbiopharmaceuticals is particularly useful for forming in-situ a cohesivesolid or semi-solid mass loaded with said drugs or biopharmaceuticalsand able to subsequently deliver in-situ by release the drugs orbiopharmaceuticals.

Example 17 illustrates the release of an anticancer agent, doxorubicinehydrochloride, from the precipitated cohesive mass obtained when aninjectable embolizing composition of the present invention including theanticancer agent is used.

In another embodiment of the present invention, the injectableembolizing composition comprises superparamagnetic iron oxidenanoparticles (SPIONs).

The injectable embolizing composition including SPIONs is particularlyuseful for forming in-situ a solid or semi-solid implant loaded withsaid SPIONs into a tumor for treating the tumor by hyperthermia.

SPIONs which are used in the injectable embolizing composition of thepresent invention may be adequately coated or encapsulated, or may beimmobilized in silica beads.

SPIONs which may be included in the injectable embolization compositionof the present invention may be commercially available SPIONs, forexample SPIONs immobilized in silica beads such as MagSilica 50-85(Evonik, Germany), or may be for example SPIONS as disclosed inWO-A-2006/125452 or by Matthieu Chastellain et al. “SuperparamagneticSilica-Iron Oxide Nanocomposites for Application in Hyperthermia” inAdvanced Engineering Materials, 6:235-241, 2004.

Example 16 illustrates the in-situ formation of an hyperthermic implantby using the injectable embolizing composition of the present inventionloaded with SPIONs immobilized in silica bead for controlled localhyperthermia,

FIG. 12 represents a graph showing that when the hyperthermic implantobtained in Example 16 is exposed to an alternating magnetic field, thetemperature increases, thus demonstrating that the injectable embolizingcomposition of the present invention loaded with SPIONs is applicablefor treatment, for example of a tumor, by hyperthermia.

In another embodiment of the present invention, the injectableembolizing composition of the present invention may be used for formingin-situ a semi-solid implant for treating urinary incontinence throughlocal tissue augmentation.

For instance, in the context of the treatment of urinary incontinence, awidespread condition among women, urethral bulking is recognized as astandard treatment.

It consists in injecting, under the bladder mucosa, a biomaterial thatcreates a bulge in the tissue, thus increasing the closure of theurethra. Collagen is used nowadays but its effect last only for a fewmonths.

Consequently, there is a need for long-lasting, non-degradable implantswhich should offer imaging ability for long-term follow-up.

Therefore, the injectable embolizing composition of the presentinvention provides an efficient alternative.

The present invention also concerns a coating composition for forming acoating on medical device comprising the iodo-benzylether-PVA of thepresent invention and a solvent solubilizing the iodo-benzylether-PVA,wherein the concentration of the iodo-benzylether-PVA in the compositionis selected in the range from 5-65% so that the composition is capableof forming a radiopaque coating after application on a medical deviceand solvent evaporation.

The coating composition of the present invention can be used to deposita radiopaque coating onto medical devices to make them visible underx-ray imaging.

Fabrication of the coating can be obtained by deposition of the coatingcomposition of the present invention followed by drying.

The thickness of the coating will depend on several factors, among themthe viscosity of the coating composition.

In the coating composition of the present invention, the solvents whichmay be used for solubilizing the iodo-benzylether-PVA comprisetetrahydrofuran, dimethylformamide, dichloromethane,N-methylpyrrolidone, dimethyl sulfoxide.

In the case of poorly biocompatible solvent such as dichloromethane,complete elimination of the solvent must be obtained before use, whichcan be obtained by drying for organic solvents having a low boilingpoint.

For example, said coating composition may be useful for coating the tipof a catheter, as reported in Example 17 and illustrated in FIG. 14.

The present invention further concerns particles, such as nanoparticlesand microparticles made of the iodo-benzylether-PVA of the presentinvention.

Nanoparticle or microparticles can be produced to help or improve theuse of x-ray imaging techniques in the medical field.

For example, radiopaque particles of the present invention may be usedas contrast agent to tag a specific tissue or to follow, upon injection,the flow of a physiological fluid.

In a preferred embodiment, the radiopaque particles of the presentinvention further contain drugs or pharmaceuticals.

Radiopaque particles loaded with drugs or biopharmaceuticals can betracked into the body after their administration, for example afterintratumoral injection.

Radiopaque particles of the present invention can be produced from theiodo-benzylether-PVA of the present invention using any technique knownto those skilled in the art of particle manufacturing.

For instance, Example 19 provides means for the fabrication ofnanoparticles of different sizes from MIB-PVA 47 kDa (DS=49%) andTIB-PVA 13 kDa (DS=53%) using the nanoprecipitation technique.

The following examples are intended to illustrate the present invention.However, they cannot be considered in any case as limiting the scope ofthe present invention.

EXAMPLES

The reactions can be monitored by thin layer chromatography (TLC) onsilica with 1/3 ethyl acetate/hexane mixture as mobile phase andobservation under UV, illumination at 254 nm wavelength.

¹H and ¹³C NMR spectra were recorded on a Brucker 300 MHz and Brucker400 MHz spectrometer respectively. Chemical shifts are given in ppm(reference δ=7.27 (CDCl₃), 2.50 (DMSO-d6) for ¹H-NMR and δ=77.1 (CDCl₃),39.5 (DMSO-d6) for ¹³C-NMR).

The degree of substitutions (DS) were calculated from the integration ofthe NMR lines of the ¹H-NMR spectra of the iodo-benzylether-PVA.

The iodine contents were calculated based on the degree of substitution,as explained in the description and confirmed by elemental analysis.

Radiopacities of iodo-benzylether-PVA were evaluated under X-rayvisualization of powdered samples and solutions.

Transmission IR spectra were recorded on a Nicolet 460 Spectrometer ESP.Pellets were prepared by pressing 1 mg of compound and 100 mg KBrpowders.

Melting points were determined by differential scanning calorimetry(DSC) on a Q200, TA Instrument.

PVA 13 kDa is a poly(vinyl alcohol) having a weight-average molar mass(Mw) of 13,000-23,000 Daltons and a degree of hydrolysis of 87-89% etwas purchased from Sigma-Aldrich® Co.

PVA 47 kDa is Mowiol® 6-98, a poly(vinyl alcohol) having aweight-average molar mass (Mw) of 47,000 Daltons, a degree of hydrolysisof 98.0-98.8%, and a viscosity of 6 mPa·s at 4% in H₂O, 20° C. and waspurchased from Sigma-Aldrich® Co.

PVA 61 kDa is Mowiol® 10-98, a poly(vinyl alcohol) having aweight-average molar mass (Mw) of 61,000 Daltons, a degree of hydrolysisof 98.0-98.8%, and a viscosity of 10 mPa·s at 4% in H₂O, 20° C. and waspurchased from Sigma-Aldrich® Co.

PVA 125 kDa is Mowiol® 20-98, a poly(vinyl alcohol) having aweight-average molar mass (M) of 12,500 Daltons, a degree of hydrolysisof 98.0-98.8%, and a viscosity of 20 mPa·s at 4% in H₂O, 20° C. and waspurchased from Sigma-Aldrich® Co.

2,3,5-triiodobenzoic acid was purchased from Changzhou Dahua Imp. AndExp. Corp. Ltd. (China).

4-iodobenzyl bromide was purchased from Sigma-Aldrich® Co.

Other reagents were purchased from commercial suppliers and used asreceived unless otherwise is noted.

THF and CH₂Cl₂ were dried by passing them on a basic activated alumina,Al₂O₃.

H₂O means de-ionized water.

Preparation Example 1 Synthesis of 2,3,5-triiodobenzyl alcohol 1

A solution (1M) of BH₃-tetrahydrofuran (75 ml, 75 mmol) was addeddropwise to a solution of 2,3,5-triiodobenzoïc acid (5 g, 10 mmol) indry tetrahydrofuran (10 ml) keeping the temperature inside the reactorbelow 2° C. under dry nitrogen gas flow. The reaction mixture wasstirred 1 h15 at 0° C., then 1 h at room temperature (18° C.), and awhite precipitate was obtained. Then a cold solution tetrahydrofuran/H₂O13:2 (26 ml) was slowly added to the crude mixture (temperaturemonitored in cooling the reactor) for hydrolysis of excess boran and thecrude mixture was neutralized by dilution in a cold solution of NaHCO₃(˜100 ml). A white precipitate appeared after a stirring of 1 h. Thesolid was recovered by filtration and washed with H₂O and cold absoluteethanol. In order to eliminate traces of ethanol after evaporation, thewhite solid was dissolved in CH₂Cl₂ then evaporated then dried undervacuum. 2,3,5-triiodobenzyl alcohol in the form of a white clean solidwas obtained in quantitative yield (4.8 g).

Mp: 156-159° C.

IR: 3186, 2904, 1524, 1400, 1368, 1235, 1144, 1047, 997, 859, 719, 675cm⁻¹

¹H-NMR (DMSO-d6): 8.16 (d, 1H, J=2.0 Hz), 7.70 (d, 1H, J=2.0 Hz), 5.69(Is, 1H, OH), 4.34 (s, 2H, CH₂)

¹³C-NMR (DMSO-d6): 69.83 (CH₂), 95.77 (Cq), 109.84 (Cq), 112.99 (Cq),134.56 (CH), 144.13 (Cq), 149.27 (CH)

Preparation Example 2 Synthesis of 2,3,5-triiodobenzyl mesylate 2

Mesyl chloride (0.6 ml, 8 mmol) was added dropwise to a suspension of2,3,5-triiodobenzyl alcohol 1 (1.94 g, 4 mmol) in dry dichloromethane(30 ml) containing diisopropylethylamine (1.4 ml, 8 mmol) at 0° C. underdry nitrogen gas flow. The reaction mixture was stirred 1 h15 at 0° C.,then cold H₂O (40 ml) was added. The resulting aqueous phase wasextracted with dichloromethane (10 ml). The combined organic extractswere washed with H₂O (8 ml) then dried (Na₂SO₄), filtered andconcentrated. The pale yellow solid was also washed with cold methanol(35 ml). 1.894 g of 2,3,5-triiodobenzyl mesylate in the form of a whiteclean solid was obtained in 84% yield.

Mp: 130-133° C.

IR: 3026, 1525, 1342, 1330, 1176, 1168, 1008, 975, 862, 836 cm⁻¹

¹H-NMR (CDCl₃): 8.23 (d, 1H, J=1.5 Hz), 7.69 (d, 1H, J=1.5 Hz), 5.23 (s,2H, CH₂), 3.11 (s, 3H, Me)

¹³C-NMR (CDCl₃): 38.29 (Me), 76.32 (CH₂), 94.72 (Cq), 110.98 (Cq),112.29 (Cq), 136.96 (CH), 140.69 (Cq), 147.48 (CH)

Preparation Example 3 Synthesis of 2,3,5-triiodobenzyl bromide 3

A solution of phosphorous tribromide (3.8 ml, 40 mmol) was addeddropwise to a solution of 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20mmol) in dry tetrahydrofuran (50 ml) at 0° C. under dry nitrogen gasflow. The reaction mixture was stirred 5 minutes at 0° C., then 20minutes at room temperature (18° C.), then cold H₂O/DCM (60/60 ml) wasadded. The resulting aqueous phase was extracted with dichloromethane(2×10 ml). The combined organic extracts were washed with NaHCO₃aq (20ml) and H₂O (20 ml) then dried (Na₂SO₄), filtered and concentrated. Thewhite solid was also washed with cold methanol (45 ml). 9.35 g of2,3,5-triiodobenzyl bromide in the form of a white clean solid wasobtained in 85% yield.

Mp: 120-121° C.

IR: 710, 866, 980, 1157, 1212, 1398, 1515, 3026 cm⁻¹

¹H-NMR (DMSO-d6): 4.81 (s, 2H, CH₂), 7.95 (d, 1H, J=2.1 Hz), 8.18 (d,1H, J=2.1 Hz)

¹³C-NMR (DMSO-d6): 42.33 (CH₂), 95.77 (Cq), 113.95 (Cq), 114.97 (Cq),137.69 (CH), 144.87 (Cq), 145.92 (CH)

Preparation Example 4 Synthesis of 2,3,5-triiodobenzyl chloride 4

Mesyl chloride (4.24 ml, 56 mmol) was added dropwise into a suspensionof 2,3,5-triiodobenzyl alcohol 1 (9.72 g, 20 mmol) in drydichloromethane (140 ml) containing diisopropylethylamine (11 ml, 64mmol) and lithium chloride (4.24 g, 100 mmol) at 0° C. under drynitrogen gas flow. The reaction mixture was stirred 5 h at roomtemperature, then cold H₂O (100 mL) was added. The resulting aqueousphase was extracted with dichloromethane (2×10 ml). The combined organicextracts were washed with NaHCO₃aq (20 ml) and H₂O (20 ml) then dried(Na₂SO₄), filtered and concentrated. The pale yellow solid was alsowashed with cold absolute ethanol (25 mL). 9.05 g of 2,3,5-triiodobenzylchloride in the form of a white clean solid was obtained in 90% yield.

Mp: 97-98° C.

IR: 680, 731, 859, 867, 1007, 1133, 1267, 1371, 1439, 1520 cm⁻¹

¹H-NMR (DMSO-d6): 4.87 (s, 2H, CH₂), 7.92 (d, 1H, J=1.9 Hz), 8.21 (d,1H, J=1.9 Hz)

¹³C-NMR (DMSO-d6): 53.58 (CH₂), 95.78 (Cq), 113.89 (Cq), 114.65 (Cq),137.74 (CH), 144.48 (Cq), 146.08 (CH)

Preparation Example 5 Synthesis of 2,3,5-tri-iodobenzoate-PVA 13 kDa(TIB/Ester-PVA 13 kDa)

The grafting reaction was adapted from the work reported in “Elaborationof radiopaque iodinated nanoparticles for in situ control of local drugdelivery” D. Ma wad, H. Mouaziz, A. Penciu, H. Méhier, B. Fenet, H.Fessi, Y. Chevalier; Biomaterials 2009, 30, 5667-5674.

The PVA 13 kDa was dissolved in dry NMP under nitrogen gas flow and asolution of triiodobenzoyl chloride in NMP was added. Then dry pyridineand DMAP were added. After 12 hours, cold water was added, a pastematerial precipitated, was filtered and washed with methanol. For thepurification step, the crude paste material was dissolved in NMP(concentration: 22 wt %) and cold ethanol was added. A paste materialprecipitated, was filtered and analyzed by NMR spectrum. The 1H NMRspectrum showed the grafted PVA free of residual reagent, and traces ofsolvents. In order to eliminate the traces of solvents, the grafted PVAwas dissolved in THF (concentration: 30 wt %) and cold water was added.A paste material precipitated, was filtered, washed with methanol anddried under vacuum. The grafted PVA was obtained as a brown solid.

¹H-NMR (DMSO-d6): 1.35-1.95 ppm (m, 5.81 au, CH₂ PVA chain, 2 (x+y)),3.81 ppm (s, 2.09 au, CH_(b) PVA chain, y), 4.21-4.67 ppm (m, 2.69 au,OH), 5.37 (s, 0.78 au, CH, PVA chain, x), 7.71 ppm (s, 1.0 au, Haromatic, x), 8.34 ppm (s, 1.0 au, H aromatic, x)

Based on NMR spectrum, TIB/Ester-PVA 13 kDa was obtained with a DS of34%.

Preparation Example 6 Synthesis of 4-mono-iodobenzoate-PVA 47 kDa (MIB/Ester-PVA 47 kDa)

The reaction conditions were the same as used for the2,3,5-tri-iodobenzoate-PVA 13 kDa in Preparation Example 5. The PVA wasdissolved in NMP and a solution of 4-mono-iodobenzoyl chloride wasadded. Then dry pyridine and DMAP were added. After 6 hours, cold waterwas added and a paste material has precipitated, was filtered and washedwith methanol. For the purification step, the crude paste material wasdissolved in NMP (concentration: 14 wt %) (the mixture is yellow butopaque and all of the particles are dissolved) and 100 mL of a solutionof NaHCO₃ was added. A solid has precipitated, was filtered and washedwith methanol. This step was repeated until the monoiodobenzoyl chloridewas eliminated. Then the solid was dissolved in NMP (concentration: 19wt %) and cold water was added. A solid has precipitated, was filteredand washed with methanol. The solid was analyzed by ¹H-NMR.

¹H NMR (DMSO-d6): 1.05-2.4 ppm (m, 5.49 au, CH₂ PVA chain, 2(x+y)), 3.81ppm (s, 1.28 au, CH_(b) PVA chain, y), 4.21-4.67 ppm (m, 0.77 au, OH),5.37 ppm (s, 1.0 au, CH_(a) PVA chain, x), 7.10-7.90 ppm (m, 4.35 au, Haromatic, 4x)

Based on NMR spectrum, MIB/Ester-PVA 47 kDa was obtained with a DS of40%.

Example 1

Grafting 2,3,5-triiodobenzyl bromide to PVA to prepare2,3,4-triiodobenzyl ether of poly(vinyl alcohol) of the presentinvention (TIB-PVA 13 kDA)

294 mg of PVA 13 kDa (6 mmol) was dissolved in 20 ml of dry NMP(concentration of PVA: 0.3 M) under nitrogen gas flow. The reactionmixture was stirred for 5 minutes at 130° C.; then the temperature wasdecreased to 50° C. 4.94 g of 2,3,5-triiodobenzylbromide 3 (9 mmol) wasadded and the reaction mixture was stirred for 10 minutes. Then, 480 mgof ground and dried NaOH (12 mmol) was added in 10 minutes. After 5hours, the mixture was cooled to room temperature and 20 ml of coldwater was added under stirring. A solid precipitate has appeared and wasfiltrated, washed with methanol and dichloromethane. 3.15 g of crudesolid was obtained and analyzed by ¹H-NMR to determine that the crudeproduct contained 56% of non-grafted triiodobenzylbromide and 30% ofgrafted PVA. In order to isolate the grafted PVA, the crude solid wasdissolved in NMP (concentration: 7 wt %) and same volume of coldmethanol was added. A paste material precipitated and was filtrated,washed with methanol and was analyzed by ¹H NMR. The purity of graftedPVA was 86%. This paste material was dissolved in NMP (concentration: 17wt %) and same volume of cold methanol was added. A paste materialprecipitated, was filtrated, washed with methanol and was analyzed by ¹HNMR. The purity of grafted PVA was 97%. In order to obtain a purity of100%, the paste material was dissolved in NMP (concentration: 17 wt %)and same volume of cold water was added. The solid precipitate wasfiltrated, washed with methanol to obtain the grafted PVA in the form ofa beige solid with a purity of 100%, as analyzed by NMR with a overallyield of 19%.

In order to eliminate residual traces of NMP contained in the graftedPVA, the grafted PVA was dissolved in THF (concentration: 13 wt %) andcold water was added. The grafted PVA (TIB-PVA 13 kDa) has precipitatedand was analyzed by ¹H-NMR.

The ¹H-NMR spectrum is represented in FIG. 1 and shows traces of THF inthe grafted PVA.

¹H-NMR (DMSO-d6): 1.51-1.85 (m, 3.8 au, CH₂ PVA chain (2(x+y)), 3.4-4.05(m, 1.5 au, CH PVA chain (x+y)), 4.16-4.52 (m, 2.4 au, CH₂ benzyl andresidual OH (2x+y)), 7.60 (s, 1.0 au, H aromatic (x)), 8.04 (s, 1.0 au,H aromatic (x))

The degree of substitution (DS) was measured from the areas under thepeaks of the NMR spectrum calculated from the integration of the NMRlines. The ratio of the area of the aromatic lines to the area of theCH₂ of PVA chain is x/2(x+y)=DS/2. Accordingly, DS was 0.54 (i.eDS=54%).

The expected iodine content as calculated from the DS was 69%, and theiodine content as confirmed by elemental analysis was 64%.

Example 2

Grafting 4-monoiodobenzyl bromide to PVA to prepare 4-monoiodobenzylether of polyvinyl alcohol) of the present invention (MIB-PVA 13 kDa)

589 mg of PVA 13 kDa (12 mmol) was dissolved in 40 ml of dry NMP undernitrogen gas flow. The reaction mixture was stirred for 5 minutes at130° C.; then the temperature was decreased to 50° C. 5.3 g of4-iodobenzyl bromide (18 mmol) was added and the reaction mixture wasstirred for 10 minutes. Then, 960 mg of ground and dried NaOH (24 mmol)was added in 10 minutes. After 4 hours, the mixture was cooled to roomtemperature and 40 ml of cold water was added under stirring. A pastematerial has appeared and was filtrated, washed with methanol anddichloromethane. 3.9 g of crude paste material was obtained and analyzedby ¹H NMR to determine that the paste material contained 44% ofnon-grafted 4-iodobenzyl bromide and 56% of grafted PVA. In order toisolate the grafted PVA, the paste material was dissolved in DMF(concentration: 50 wt %) and two volumes of cold methanol was added. Apaste material has precipitated and was filtrated, washed with methanoland was analyzed by ¹H-NMR. The purity of grafted PVA was 80%. Thispaste material was dissolved in THF (concentration: 50 wt %) and threevolumes of cold methanol was added. A paste material has precipitated,was filtrated, washed with methanol and was analyzed by ¹H NMR. Thepurity of grafted PVA was 95%. The paste material was dissolved in THF(concentration: 28 wt %) and two volumes of cold methanol was added. Apaste material has appeared, was filtrated, and washed with methanol.The purity was 98%. In order to obtain a purity of 100%, the grafted PVAwas dissolved in THF (concentration: 29 wt %) and three volumes of coldwater was added. A paste material has appeared, was filtrated, andwashed with methanol. After drying, the grafted PVA (MIB-PVA 13 kDa) wasobtained in the form a an orange solid in an overall yield of 24%. The¹H NMR spectrum of the MIB-PVA 13 kDa is represented in FIG. 2.

¹H-NMR (DMSO-d6): 1.34-1.90 (m, 3.8 au, CH₂ PVA chain (2(x+y)),3.58-3.78 (m, 1.5 au, CH PVA chain (x+y)), 4.23-4.48 (m, 2.4 au, CH₂benzyl and residual OH (2 x+y)), 7.00 (s, 2.0 au, H aromatic (2×)), 7.54(s, 2.0, H aromatic (2×))

The degree of substitution (DS) was measured from the areas under thepeaks of the NMR spectrum calculated from the integration of the NMRlines. The ratio of the area of the aromatic lines to the area of theCH₂ of PVA chain is 2×/2(x+y)=DS. Accordingly, DS was 0.56 (i.e DS=56%).

The expected iodine content as calculated from the DS was 43%, and theiodine content confirmed by elemental analysis was 43%.

Example 3 Precipitation Tests

The TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP atconcentrations of 10% w/w and 33% w/w, and these two injectablecompositions were precipitated in water using a syringe with a needle of0.8 mm diameter. The results obtained are shown in FIG. 3 a and FIG. 3b.

As shown in FIG. 3 a, the injectable composition containing 10% w/w ofTIB-PVA 13 kDa dissolved in NMP did not precipitate as a cohesive mass,and therefore is not appropriate as injectable embolizing composition ofthe present invention.

However, as shown in FIG. 3 b, the injectable composition containing 33%of TIB-PVA 13 kDa dissolved in NMP precipitates as a cohesive mass, andtherefore is appropriate as injectable embolizing composition of thepresent invention.

Further, the MIB-PVA 13 kDa obtained in Example 2 was dissolved in DMSOat a concentration of 33% w/w and this injectable composition wasprecipitated in water using a syringe of 1 ml with a needle of 0.9 mm.

As shown in FIG. 4, the injectable composition containing 33% w/w ofMIB-PVA dissolved in DMSO precipitates as a cohesive mass, and thereforeis appropriate as injectable embolizing composition of the presentinvention.

Additional experiments shown that all compositions containing TIB-PVA 13kDa dissolved in NMP or MIB-PVA 13 kDa dissolved in DMSO precipitate asa cohesive mass for concentrations higher than 20% (w/w).

Example 4 Embolizing Compositions and Viscosities

As the viscosity is an important parameter for the choice of theconcentration of the iodo-benzylether-PVA in injectable compositions forembolization, the following experiments have been performed.

The MIB-PVA 13 kDa obtained in Example 2 was dissolved in DMSO atconcentrations varying from 20 to 50% w/w, and the viscosities of thesolutions were measured.

The TIB-PVA 13 kDa obtained in Example 1 was dissolved in NMP atconcentrations varying from 20 to 50% w/w, and the viscosities of thesolutions were measured.

Viscosities were measured at a temperature of 25° C. using a cone-platerheometer (Bohlin CV0120 from Malvern Instruments).

FIG. 5 shows the increase of the viscosity when the concentration of theiodo-benzylether-PVA obtained from PVA 13 kDa in the specified solventincreases.

Therefore, FIG. 5 shows that the viscosity of the embolizingcompositions can be tailored by iodo-benzylether-PVA concentration,iodo-benzylether-PVA type, and solvent nature to obtain the highviscosity (ca 500 mPa·s) required for aneurysm embolization as well asthe lower viscosity (ca 50 mPa·s) adequate for embolization of smallcapillaries.

For comparison, the Onyx™ 34 commercial embolizing composition has aviscosity of 55 mPa·s.

Example 5 Radiopacity of Embolizing Compositions

Solutions of MIB-PVA 13 kDa obtained in Example 2 and TIB-PVA 13 kDaobtained in Example 1 at a concentration of 33% w/w in NMP were pouredin radiolucent 1 ml Eppendorfs. X-ray absorption was measured on acomputerized tomograph scan (CT-scan, Skyscan 1076, Skyscan, Belgium)using a 0.5 mm aluminum window, under 50 kV and 200 μA. 180 degreestomograms were acquired and reconstructed (Nrecon 1.5.1.4, Skyscan,Belgium), and pixel gray level was averaged over the whole embolic image(imageJ program, NIH). For calibration in Hounsfied units (HU), water(HU=0) and air (HU=−1000) were used.

As shown in FIG. 6, the radiopacity of the composition containing 33%w/w of TIB-PVA 13 kDa of Example 1 in NMP is comparable to that ofcommercial liquid embolizing compositions (Onyx™ 34 and Onyx™ 18)containing 20% of radiopaque tantalum.

However, the embolizing composition containing 33% w/w of MIB-PVA 13 kDaof Example 2 in NMP shows lower radiopacity, as expected from its loweriodine content.

Noteworthy, if left at rest for more than a few minutes, tantalum inOnyx™ sedimented, leading to highly inhomogeneous radiopacity.

From these data, it is expected that a compositions containing 55% w/wof 4-monoiodobenzyl ether of poly(vinyl alcohol) in NMP would have aradiopacity comparable to the Onyx™ compositions.

Example 6 Embolization of a Model Aneurysm

Two injectable embolizing compositions of the present invention andOnyx™ 34 commercial composition were tested for their ability to fill ananeurysm model. We used as a model a 10 mm-diameter sphere affixed to aglass tube. The model was flushed with saline using a rotary pump undera 30 cm/s flow speed mimicking blood flow. The injectable embolizingcomposition was injected into the aneurysm model with a 22 G needle.

FIG. 7 a shows embolization of an aneurysm model with an injectableembolizing composition (A) of the present invention containing 33% w/wof TIB-PVA 13 kDa obtained in Example 1 in NMP.

FIG. 7 b shows embolization of a aneurysm model with an injectableembolizing composition (B) of the present invention containing 33% w/wof MIB-PVA 13 kDa obtained in Example 2 in NMP.

FIG. 7 c shows embolization of an aneurysm model with Onyx™ 34commercial embolizing composition.

These FIGS. 7 a, 7 b and 7 c clearly illustrate the ability of theintrinsically radiopaque injectable embolizing compositions (A, B) tofill completely the sphere with a compact mass, in a manner comparableto the commercially available injectable embolizing composition Onyx™34. (C).

For all injectable embolizing compositions A, B and C, a cohesive masswas formed under flow within 3 minutes.

Example 7 Synthesis of 2,3,5-tri-iodobenzylether-PVA from PVA 13 kDa(TIB-PVA 13 kDa)

447 mg of PVA 13 kDa (9 mmol, 1 eq) was dissolved in 30 ml of dry NMP(concentration of PVA: 0.3M) under nitrogen gas flow. The reactionmixture was stirred for 5 minutes at 130° C.; then the temperature wasdecreased to 50° C. 727 mg of ground and dried NaOH (18 mmol, 2 eq) wasadded and the mixture was stirred for 10 minutes. Then, 5 g of2,3,5-triiodobenzyl bromide (9 mmol, 1 eq) was added. After 30 minutes,the mixture was cooled to room temperature and 30 ml of cold water wasadded under stirring. A solid precipitate appeared, was filtered andwashed with methanol. After conventional steps of purification, 800 mgof TIB-PVA 13 kDa including 26% of residual NMP was obtained(representing 208 mg of NMP and 592 mg of TIB-PVA 13 kDa).

¹H-NMR (DMSO-d6): 1.35-1.76 ppm (m, 3.74 au, CH₂ PVA chain (2(x+y)), 1.9ppm (q, 4.65 au, CH₂)*, 2.1 ppm (t, 3.82 au, CH₂)*, 2.6 ppm (s, 5.63 au,CH₃)*3.6-4.0 ppm (m, 1.79 au, CH PVA chain (x+y)), 4.1-4.6 ppm (m, 2.71au, CH₂ benzyl and residual OH (2x+y)), 7.6 ppm (s, 1.04 au, H aromatic(x)), 8.06 ppm (s, 1.0 au, H aromatic (x))

*Residual NMP

The DS calculated from the NMR lines according to the method of Example1 was 53%.

Example 8 Synthesis of 2,3,5-tri-iodobenzylether-PVA from PVA 47 kDa(TIB-PVA 47 kDa)

The same synthesis method as in Example 7 was used in order to graft the2,3,5-triiodobenzyl bromide with the PVA 47 kDa. After conventionalsteps of purification, TIB-PVA 47 kDa including residual NMP wasobtained.

¹H NMR (DMSO-d6): 1.35-1.76 ppm (m, 3.42 au, CH₂ PVA chain (2(x+y)), 2.1ppm (t, 3.07 au, CH₂)*, 3.6-4.0 ppm (m, 1.81 au, CH PVA chain (x+y)),4.1-4.6 ppm (m, 2.72 au, CH₂ benzyl and residual OH (2x+y)), 7.59 ppm(s, 1.0 au, H aromatic (x)), 8.04 ppm (s, 1.0 au, H aromatic (x))

*Residual NMP

The DS calculated from the NMR lines according to the method of Example1 was 58%.

Example 9 Synthesis of 2,3,5-tri-iodobenzylether-PVA from PVA 61 kDa(TIB-PVA 61 kDa)

The same synthesis method as in Example 7 was used in order to graft the2,3,5-triiodobenzyl bromide with the PVA 61 kDa PVA. After conventionalsteps of purification, TIB-PVA 61 kDa including residual NMP wasobtained.

¹H NMR (DMSO-d6): 1.35-1.76 ppm (m, 4.33 au, CH₂ PVA chain (2(x+y)), 2.1ppm (t, 6.36 au, CH₂)*, 3.6-4.0 ppm (m, 2.23 au, CH PVA chain (x+y)),4.1-4.6 ppm (m, 2.97 au, CH₂ benzyl and residual OH (2x+y)), 7.59 ppm(s, 1.0 au, H aromatic (x)), 8.05 ppm (s, 1.0 au, H aromatic (x))

*Residual NMP

The DS calculated from the NMR lines according to the method of Example1 was 46%.

Example 10 Synthesis of 4-mono-iodobenzylether-PVA from PVA 13 kDa(MIB-PVA 13 kDa)

825 mg of PVA 13 kDa was dissolved in 55 ml of dry NMP under a nitrogenflow at 130° C. Then the temperature was decreased to 50° C. and 5 g of4-monoiodobenzyl bromide was added. After 10 minutes, 1.35 g of driedsodium hydroxide was added. After 5 hours of reaction time, cold waterwas added and a paste material has appeared. The sticky paste could notbe filtrated. Water was easily removed because the material was struckto the walls of the flask. After water was poured out, the pasty residuewas washed with methanol and dried. After conventional steps ofpurification, MIB-PVA 13 kDa including residual NMP was obtained.

¹H-NMR (DMSO-d6): 1.35-1.76 ppm (m, 2.9 au, CH₂ PVA chain (2(x+y)), 1.9ppm (q, 1.02 au, CH₂)*, 2.1 ppm (t, 1 au, CH₂)*, 2.7 ppm (s, 1.5 au,CH₃)*, 3.6-3.79 ppm (m, 1.6 au, CH PVA chain (x+y)), 4.38-4.48 ppm (m,2.6 au, CH₂ benzyl and residual OH (2x+y)), 7.03 ppm (s, 2.0 au, Haromatic (2×)), 7.55 ppm (s, 2.0 au, H aromatic (2×))

*Residual NMP

The DS calculated from the NMR lines according to the method of Example2 was 69%.

Example 11 Synthesis of 4-mono-iodobenzylether-PVA from PVA 47 kDa(MIB-PVA 47 kDa)

The same synthesis method as in Example 10 was used in order to graftthe 4-monoiodobenzyl bromide with the PVA 47 kDa. After conventionalsteps of purification, MIB-PVA 47 kDa including residual NMP wasobtained.

¹H NMR (DMSO-d6): 1.35-1.76 ppm (m, 4.1 au, CH₂ PVA chain (2(x+y)), 1.9ppm (q, 0.9 au, CH₂)*, 2.1 ppm (t, 0.9 au, CH₂)*, 2.7 ppm (s, 1.3 au,CH₃)*, 3.3 ppm (t, 0.98 au, CH₂)*, 3.6-3.79 ppm (m, 1.9 au, CH PVA chain(x+y)), 4.38-4.48 ppm (m, 2.9 au, CH₂ benzyl and residual OH (2x+y)),7.03 ppm (s, 2.0 au, H aromatic (2×)), 7.55 ppm (s, 2.0 au, H aromatic(2×))

*Residual NMP

The DS calculated from the NMR lines according to the method of Example2 was 49%.

Example 12 Synthesis of 4-mono-iodobenzylether-PVA from PVA 61 kDa(MIB-PVA 61 kDa)

The same synthesis method as in Example 10 was used in order to graftthe 4-monoiodobenzyl bromide with the PVA 61 kDa. After conventionalsteps of purification, MIB-PVA 61 kDa including residual NMP wasobtained.

¹H-NMR (DMSO-d6): 1.35-1.76 ppm (m, 3.9 au, CH₂ PVA chain (2(x+y)), 1.9ppm (q, 2.4 au, CH₂)*, 2.1 ppm (t, 2.2 au, CH₂)*, 2.7 ppm (s, 3.3 au,CH₃)*, 3.6-3.79 ppm (m, 1.4 au, CH PVA chain (x+y)), 4.38-4.48 ppm (m,2.7 au, CH₂ benzyl and residual OH (2x+y)), 7.00 ppm (s, 1.9 au, Haromatic (2×)), 7.54 ppm (s, 2.0 au, H aromatic (2×))

*Residual NMP

The DS calculated from the NMR lines according to the method of Example2 was 51%.

Example 13

Grafting 4-monoiodobenzyl bromide and 2,3,5-triiodobenzyl bromide on PVA47 kDa to prepare the polymer with mixed grafted units(4-monoiodobenzyl-ether)(2,3,5-triiodobenzylether)-PVA 47 kDa (MTIB-PVA47 kDa)

The synthesis was carried out in a flame-dried 3-necked flask and underN₂-atmosphere. Poly(vinyl alcohol) (MW=47000, 80 mmol of monomer-units,3.52 g) was placed in the reaction flask which was then N₂-vacuum purgedtwice. Anhydrous NMP (280 mL) was transferred from a sealed bottle tothe reaction flask using a canula. The mixture was stirred for 30minutes at 130° C. in order to dissolve all of the polymer. The mixturewas subsequently cooled and stirred at 50° C. NaOH (2 eq., 160 mmol, 6.4g), which was freshly ground from pellets into a fine powder, was addedin one go. The mixture was stirred at 50° C. for 30 minutes, resultingin a colour change of the solution from yellow to brown. A mixture of4-iodobenzyl bromide (0.5 eq., 40 mmol, 11.9 g) and 2,3,5-triiodobenzylbromide (0.5 eq., 40 mmol, 22.0 g), obtained by mixing the two solids ina beaker with a spatula, were added as a powder in one go. This resultedin a rapid colour change from brown back to yellow. The mixture wasstirred for 1 hour. After cooling to room temperature, the polymer wasprecipitated by adding the solution dropwise to a well-stirred volume ofdemi-water (2.8 L), which resulted in the dissolution of white solidflakes. The mixture was then filtered over a P1-glassfilter, the whitecrude material was washed with another 500 mL demi-water andsubsequently twice with 500 mL acetone. The crude product was dried overnight under vacuum, and redissolved in THF (200 mL). The polymer wasthen purified via precipitation using toluene as non-solvent.Transferring the THF-solution dropwise to a well-stirred volume oftoluene (2 L) yielded white milky mixture, which was filtered over aP4-glassfilter. The white solid material was then washed with 500 mLacetone and dried over night under vacuum (˜10⁻² mbar) at 100° C.,providing 11.5 g of the product as a light-brown solid material.

The DS is calculated from the ¹H-NMR spectrum recorded in DMSO-d6containing a small quantity of water represented in FIG. 8. Thefollowing broad signals with chemical shifts of the maxima of thesignals are identified:

1. S₁ δ 8.0-8.1 ppm CH (TIB-Phenyl, para position) 2. S₂ δ 7.5-7.6 ppmCH (TIB-Phenyl, ortho position) 3. S₂ δ 7.5-7.6 ppm 2 × CH (MIB-Phenyl,meta position) 4. S₃ δ 6.9-7.0 ppm 2 × CH (MIB-Phenyl, ortho position)5. S₄ δ 4.3-4.4 ppm CH₂ (TIB-Benzyl) 6. S₄ δ 4.3-4.4 ppm CH₂(MIB-Benzyl) 7. S₄ δ 4.3-4.4 ppm OH (Backbone PVA) 8. S₅ δ 3.7-3.8 ppmCH (Backbone PVA) 9. S₆ δ 3.3-3.4 ppm H₂O (Trace water) 10. S₇ δ 2.4-2.5ppm CHD₂ (DMSO-d6) 11. S₈ δ 1.4-2.6 ppm CH₂ (Backbone PVA)

The degrees of substitution (DS) for MIB and TIB separately (DS_(MIB)and DS_(TIB), respectively) are calculated as:DS_(MIB) =S ₃ /S ₈DS_(TIB)=2S ₁ /S ₈

The overall degree of substitution is DS=DS_(MIB)+DS_(TIB)

The DS calculated from NMR data are DS_(MIB)=0.3 (30%) and DS_(TIB)=0.3(30%).

The % I is given by

${\%\mspace{14mu} I} = {\frac{{DS} \times M_{iodine} \times ( {{n_{1} \times p} + {n_{2} \times ( {1 - p} )}} )}{\begin{matrix}{{M_{{non}\text{-}{grafted}} \times ( {1 - {DS}} )} +} \\{( {{M_{{grafted} - 1} \times p} + {{xM}_{{grafted} - 2}( {1 - p} )}} ) \times {DS}}\end{matrix}} \times 100}$whereinn₁: number of Iodine atoms on aromatic ring of iodobenzyl unit #1n₂: number of Iodine atoms on aromatic ring of iodobenzyl unit #2M_(grafted-1) molar mass of iodobenzyl unit #1M_(grafted-2) molar mass of iodobenzyl unit #2p mole fraction of iodobenzyl unit #1; p=DS₁/(DS₁+DS₂)

The DS calculated from the NMR lines of MTIB-47 kDa PVA was 60%.

The % I calculated from the DS of MTIB-47 kDa PVA was 62%.

Example 14 Embolization Capability of Various Radiopaque Polymer orBlend of Polymers Formulations According to the Present Invention Usinga Hydrogel Model

Embolization formulations of the present invention based on solution of4-mono-iodobenzyl-PVA (MIB) and 2,3,5-tri-iodobenzyl-PVA (TIB) weresynthesized from PVA of various molar masses (13,000-23,000, 47,000,61,000 and 125,000 g/mol abbreviated 13 kDa PVA, 47 kDa PVA, 61 kDa PVAand 125 kDa PVA).

The solutions were made by dissolving each of the polymers in NMP at 33%w/w final concentration (otherwise mentioned).

In addition, mixtures of MIB-PVA 47 kDa and TIB-PVA 47 kDa in variousratio (MIB-PVA:TIB-PVA 25:75, 40:60, 50:50, 60:40, 75:25 in weight %)were also evaluated.

Degrees of substitution (DS) of the iodo-benzylether-PVA of the presentinvention used in this Example were 53% for MIB-PVA 47 kDa, 58% forTIB-PVA 47 kDa, 67% for MIB-PVA 61 kDa, 58% for the TIB-PVA 61 kDa and61% for the TIB-PVA 125 kDa.

Heating at 90° C. was used to accelerate dissolution. The liquidembolizing formulations were tested in a hydrogel model made ofpolyvinyl alcohol (see FIGS. 9 a and 9 b). A 3 mm-diameter hole in thehydrogel was fed with saline flow (10 mL/min) using a pump to mimiccapillary blood flow. A catheter was inserted and a flow diverterlimited pressure buildup upon embolization.

Upon injection of ca 0.1 mL of each embolic, cylinder-shaped polymerplugs could be formed, resulting in capillary obstruction.

FIGS. 9 a and 9 b show the typical plugs obtained with the formulationof the present invention containing TIB-PVA 47 kDa at concentrations of30% and 35% in NMP.

The highest polymer concentration did show slightly better embolizationability in this specific setting, as well as an increased radiopacity.

In case of backward reflux, stopping the injection for 1 to 3 mingenerally allowed to continue the embolization distally.

The catheters could generally be withdrawn easily, the MIB-PVA andTIB-PVA of the present invention demonstrating little adhesion to thecatheters.

The TIB-PVA 47 kDa, TIB-PVA61 kDa and TIB-PVA 125 kDa could embolize thehydrogel capillary model in a similar manner, although the low molarmass polymer, which demonstrates the lower solution viscosity, may bepreferred for the embolization of small vascular structures. MIB-PVA 47kDa and MIB-PVA 61 kDa could similarly embolize the hydrogel capillary,although showing a slower precipitation than the TIB-PVA.

Mixtures of MIB-PVA and TIB-PVA at various ratios were also able toobstruct totally the capillary following their precipitation.

An increasingly faster precipitation was observed with increasingTIB-PVA contents, as well as harder but more brittle precipitated cast.

These results indicates that a whole family of formulations can beobtained using MIB-PVA and TIB-PVA, tailoring their properties byadapting polymer molar mass, concentration and MIB-PVA/TIB-PVA ratio.

Example 15 Embolization Capability of PVA Polymers Grafted with Mixedmono-iodo and tri-iodobenzyl Groups

A MTIB-PVA 47 kDa was obtained from Example 13 using equal molar ratioof 4-mono-iodobenzyl bromide and 2,3,5-triiodobenzyl bromide for thesynthesis, corresponding to a MIB:TIB 38:62 wt % ratio. PVA 47 kDastarting material could be substituted to DS=60%. A liquid embolicformulation was made by dissolving the MTIB-PVA 47 kDa in NMP at 33% w/wfinal concentration. Heating at 90° C. was used to acceleratedissolution. The liquid formulations were tested in a hydrogel modelmade of polyvinyl alcohol as show in the previous Example 14. Uponinjection of ca 0.1 mL, the polymer solution in NMP could embolize thelumen of the hydrogel capillary. Polymer plugs could be formed,provoking obstruction and flow arrest. The catheter could be withdrawneasily. These results points out that a whole family of formulations canbe obtained using MTIB-PVA polymers, tailoring their properties byadapting polymer molar mass, concentration and molar ratio of4-mono-iodobenzyl bromide and 2,3,5-triiodobenzyl bromide.

Example 16 In Situ Forming Embolizing Compositions Added withSPIONs-Containing Silica Beads for Controlled, Local Hyperthermia

A solution of MIB-PVA 47 kDa having a DS of 56% was dissolved at 33% w/win NMP. Silica beads loaded with superparamagnetic iron oxidenanoparticles (Degussa MagSilica 50-80) were added to this solution at aconcentration of 20% w/V. The viscous liquid obtained could be injectedthrough a 21 G needle, forming a semi-solid, smooth and brown polymerball within 3 min (see FIGS. 11 a and 11 b). Injection in a hydrogelmodel of a 3-mm diameter straight vessel (similarly to Example 14)demonstrated the ability of this formulation to stop the 10 ml/min flow,mimicking the embolization of a natural vessel.

The paste was precipitated into small cylinders, 6 mm diameter. Thisimplant was inserted into an adiabatic calorimeter at room temperatureand submitted to an alternating magnetic field of 9 mT, 141 kHz(Huttinger TIG-2.5/300) during five minutes. The temperature recorded byoptical probes showed a fast increase leveling to a plateau temperatureincrease of DT=+16.6° C. as shown in FIG. 12.

The fast increase with a slope of 16° C./min corresponds to a powerdissipation of 5.1 W/g of iron oxide. Such a temperature increase isexpected to lead in vivo to thermoablation of surrounding tissues.

Example 17 Loading and Release of an Anticancer Agent from aPrecipitated Radiopaque Polymer Mass

Doxorubicine hydrochloride was dissolved in N-methylpyrrolidone (NMP, at25 mg/mL). TIB-PVA 47 kDa having a DS of 58% was added at 33% w/w finalconcentration. The solution was injected into cylindrical alginate moldsto produce 6-mm diameter plugs (ca 0.3 g each). The doxorubicine-loadedsamples were incubated in 100 mL saline at 37° C. under agitation.Doxorubicine was quantified by measurements of the optical absorption ofthe supernatant at 479 nm wavelength. FIG. 13 shows the obtained gradualrelease of the anticancer agents over 3 days.

Example 18 Coating of Medical Devices with Radiopaque Polymer Solution

A radiopaque coating was deposited onto a catheter tip by dipping andsolvent evaporation. Briefly, TBI-PVA 47 kDa having a DS of 58% weredissolved in NMP at 40° C. at a final concentration of 33% w/w. The tipof a catheter (Cordis Envoy GC) was dipped for 5 s into the radiopaquepolymer solution, withdrawn and dried at room temperature, keeping thecatheter under axial rotation to obtain an even coating. The tip coatedwith TIB-PVA 47 kDa is illustrated in FIGS. 14 a and 14 b. Radiopaqueand catheter polymers were bound together by virtue of solventevaporation. Other solvents were assessed, such as DMSO, leading tosimilar radiopaque coatings.

Example 19 Fabrication of Nanoparticles from Radiopaque Iodo-Benzyletherof the Present Invention by Nanoprecipitation

Radiopaque nanoparticles were prepared by the nanoprecipitation methodas follows: 100 mg of MIB-PVA 47 kDa having a DS of 49% was dissolved inTHF (20 ml) at room temperature to form the diffusing phase. Thediffusing phase was then added by means of a syringe to the dispersingphase constituted of phosphate buffered saline (PBS, 40 ml) containing0.25% surfactant Pluronic™ F68 under stirring. The aqueous phase turnedmilky as the organic phase was poured, leading to a homogeneous milkydispersion at the end. THF was evaporated under reduced pressure. Themean diameter of the nanoparticles, as measured using a Malvern NanoZSinstrument, was 170 nm, with a monomodal distribution.

The same method was used to produce particles with TIB-PVA 13 kDa havinga DS of 53%.

The following Table, showing the TIB-PVA 13 kDa nanoparticle diameter asa function of the concentration of TIB-PVA 13 kDa in the diffusing phaseor the concentration of Pluronic F68 in PBS, further demonstrates thatnanoparticle diameter could be tailored by varying the concentration ofTIB-PVA in the diffusing phase or the concentration of Pluronic F68 inPBS. Smaller particles, in the 50-90 nm diameter range, could beobtained by using pure water instead of PBS.

Concentration TIB-PVA - Pluronic ® Diameter of nanoparticles (nm)0.1%-0.5% 300 0.5%-0.5% 170 0.25%-0.25% 240 0.25%-0.5%  176   1%-0.75%113  1%-0.1% 108

Example 20 Comparative Degradation of Radiopaque Iodo-Benzylether-PVA(Ether) Versus Radiopaque Iodobenzoate-PVA (Ester) Nanoparticles

1. Degradation of MIB-PVA 47 kDa-Based Nanoparticles

Polymer degradation was monitored through the absorbance of the expecteddegradation product, 4-monoiodobenzoic acid. Polymer nanoparticles wereused for their high specific area. For comparison with ethers, esters ofradiopaque polymers were prepared in Preparations Examples 5 and 6(Elaboration of radiopaque iodinated nanoparticles for in situ controlof local drug delivery. D. Mawad, H. Mouaziz, A. Penciu, H. Méhier, B.Fenet, H. Fessi, Y. Chevalier; Biomaterials 2009, 30, 5667-5674).Nanoparticles of MIB-PVA 47 kDa prepared in Example 11 and MIB/Ester-PVA13 kDa prepared in Preparation Example 6 (DS=49% and 40%, respectively)were then produced by nanoprecipitation in PBS as described in theExample 19, both with a mean diameter of ca. 170 nm.

In order to study the released degradation products, the nanoparticlessuspensions were incubated at 37° C. in phosphate-buffered saline (PBS).At given time points, the nanoparticles were collected by centrifugationand the supernatants of centrifuged suspensions were analyzed by UVabsorbance at 250 nm wavelength—the absorbance maxima of4-monoiodobenzoic acid. FIG. 15 displays the time-evolution of theabsorbance, reflecting the release of degradation products. Whereas nomeasurable release was observed with the ether-based nanoparticles aftertwo months, a clear increase was rapidly observed for the ester-basesnanoparticles, showing a fast degradation of the ester-based polymer.These results indicated that the ether-based nanoparticles are stable inPBS even after one month, whereas the ester-based nanoparticles are not.

2. Degradation of TIB-PVA 13 kDa-Based Nanoparticles

Nanoparticle degradation testing was repeated using the same methods,with TIB-PVA 13 kDa obtained in Example 7 and TIB/Ester-13 kDa obtainedin Preparation Example 5 (DS=53% and 34%, respectively). Nanoparticlesof ca. 170 nm diameter were produced in PBS for both polymers. Theabsorbance wavelength was fixed at 229 nm, corresponding to the peakabsorption of the expected degradation product, 2,3,5-tri-iodobenzoicacid. As described on the FIG. 16, the absorbance of the estersupernatant increased slowly until 0.16 after one month, correspondingto the release of 8% of the iodinated groups. No measurable release wasobserved with the ether polymer. These results indicate that theether-based nanoparticles ether are stable in PBS even after one month,whereas the ester-based nanoparticles are not.

The invention claimed is:
 1. A radiopaque, non-biodegradable,water-insoluble iodinated benzyl ether of poly(vinyl alcohol) consistingof a poly(vinyl alcohol) (PVA) having covalently grafted thereoniodinated benzyl groups comprising from 1 to 4 iodine atoms per benzylgroup as the only substituents wherein a grafted repeating unit hasformula (I)

wherein n is from 1 to
 4. 2. The iodo-benzylether-PVA according to claim1, wherein the iodo-benzylether-PVA has a degree of substitution (DS) ofat least 0.2.
 3. The iodo-benzylether-PVA according to claim 1, whereinthe iodo-benzylether-PVA has an iodine content of at least 40% (w/w). 4.The iodo-benzylether-PVA according to claim 1, wherein all the graftediodinated benzyl groups are identical iodinated benzyl groups.
 5. Theiodo-benzylether-PVA according to claim 4, wherein each benzyl groupcomprises one iodine atom on C-4 position.
 6. The iodo-benzylether-PVAaccording to claim 4, wherein each benzyl group comprises 3 iodine atomson C-2, C-3 and C-5 positions.
 7. The iodo-benzylether-PVA according toclaim 1, wherein the grafted iodinated benzyl groups are two or moredifferent iodinated benzyl groups having a different number of iodineatoms.
 8. A process for preparing the iodo-benzylether-PVA of claim 1,said process comprising reacting a 0-100% hydrolyzed poly(vinyl alcohol)as a starting PVA with an iodinated benzyl derivative comprising from 1to 4 iodine atoms per benzyl group as the only substituents in a polaraprotic solvent in the presence of a base in anhydrous conditions,wherein the iodinated benzyl derivative is selected from the groupconsisting of an iodinated benzyl chloride, an iodinated benzyl bromide,an iodinated benzyl mesylate and mixtures thereof.
 9. The processaccording to claim 8, wherein said process comprises reacting a 75-100%hydrolyzed poly(vinyl alcohol) as the starting PVA.
 10. The processaccording to claim 8, wherein said starting PVA has an average molarmass (M) ranging from 5,000 to 200,000 Daltons.
 11. The processaccording to claim 8, wherein the iodinated benzyl derivative is amixture of two or more different iodinated benzyl derivatives having adifferent number of iodine atoms.
 12. The process according to claim 8,wherein the iodinated benzyl derivative is selected from the groupconsisting of 4-iodobenzylbromide and 2,3,5-triiodobenzylbromide, or amixture thereof.
 13. The process according to claim 8, wherein the polaraprotic solvent is N-methylpyrrolidone (NMP) and the base is sodiumhydroxide.
 14. An injectable embolizing composition comprising theiodo-benzylether-PVA as defined in claim 1 and a water-miscible,biocompatible solvent solubilizing the iodo-benzylether-PVA, wherein theconcentration of the iodo-benzylether-PVA in the composition is selectedin the range of 5-65 w/w % so that the composition forms a cohesive massupon contact with a body fluid by precipitation of theiodo-benzylether-PVA.
 15. The injectable embolizing compositionaccording to claim 14, wherein the concentration of theiodo-benzylether-PVA in the composition is selected in the range of20-50 w/w %.
 16. The injectable embolizing composition according toclaim 14, wherein the solvent is selected from dimethylsufoxide (DMSO),N-methylpyrrolidone (NMP) and glycofurol.
 17. The injectable embolizingcomposition according to claim 14, comprising two or more differentiodo-benzylether-PVAs, wherein the grafted iodinated benzyl groups areidentical iodinated benzyl groups, and wherein each benzyl groupcomprises one iodine atom on C-4 position or 3 iodine atoms on C-2, C-3and C-5 positions, and combinations thereof.
 18. The injectableembolizing composition according to claim 14, further comprisingsuperparamagnetic iron oxide nanoparticles (SPIONs).
 19. A coatingcomposition for forming a coating on a medical device comprising theiodo-benzylether-PVA as defined in claim 1 and a solvent solubilizingthe iodo-benzylether-PVA, wherein the concentration of theiodo-benzylether-PVA in the composition is selected in the range of 5-65w/w % so that the composition forms a radiopaque coating afterapplication on a medical device and solvent evaporation.
 20. Radiopaquenanoparticles and microparticles formed of the iodo-benzylether-PVAaccording to claim 1.